MMP-12 inhibitors

ABSTRACT

A compound of the formula (I): 
                 
 
wherein R 1  is hydroxy and the like; R 2  is optionally substituted lower alkyl and the like; R 3  is hydrogen atom and the like; R 4  is optionally substituted arylene and the like; R 5  is —C≡C— and the like; R 6  is optionally substituted naphtyl and the like
 
its optically active substance, its prodrug, their pharmaceutically acceptable salt, or solvate thereof.

TECHNICAL FIELD

This invention relates to sulfonamide derivatives, especiallysulfonamide derivatives which selectively inhibit matrixmetalloproteinases-12.

BACKGROUND ART

An extracellular matrix, consisting of collagen, fibronectin, laminin,proteoglycan, etc., has a function to support tissues, and plays a rolein propagation, differentiation, adhesion, or the like in cells.Metalloproteinases which are protease having a metal ion in the activecenter, especially matrix metalloproteinases (MMP), are concerned withthe degradation of the extracellular matrix. Many types of MMP, fromMMP-1 (collagenase type I) to MMP-23, have been reported as enzymesworking for the growth, remodeling of tissues, etc. under usualphysiological conditions. It is reported, however, that the progressionof various kinds of diseases involving breakdown and fibrosis of tissues(e.g., osteoarthritis, rheumatoid arthritis, corneal ulceration,periodontitis, metastasis and invasion of tumor, and virus infection(HIV infection)) is related with increase of the manifestation oractivity of the above-mentioned enzyme.

Matrix metalloproteinases-12 (MMP-12) is produced from macrophage andhas a character which decomposes elastin and is different from otherMMPs'. It is known that this enzyme cleaves collagen type I, collagentype IV, fibronectin, laminin and the like. It is also described inSCIENCE 1997, 277(26), 2002-2004 and Exp. Opin. Ther. Patents(1999)9(7),851-895 and the like that MMP-12 plays a role in pulmonaryemphysema. Therefore, MMP-12 is considered to be involved in thepathogenesis of chronic obstructive pulmonary disease (COPD) which ischaracterized by respiratory obstruction caused by pulmonary emphysemaor chronic bronchitis. It is suggested in Exp. Opin. Ther. Patents(1999) 9(7),851-895 and the like that MMP-12 relates to diseases ofmetastatic carcinoma, atherosclerosis and the like.

Sulfonamide derivatives having an inhibitory activity against, MMP aredescribed in WO97/27174, WO99/04780 and the like.

No compound having an inhibitory activity against MMP-12 is known.

DISCLOSURE OF INVENTION

The inhibition of such MMP-12 activities is considered to contribute tothe improvement and prevention of the above diseases caused by orrelated to the activity. Therefore, the development of MMP-12 inhibitorshas been desired.

In the above situation, the inventors of the present invention havefound that certain sulfonamide derivatives having a bisyclic ortricyclic condensed ring at a terminal position have a potent activityto inhibit MMP-12.

The present invention relates to:

-   1) A compound of the formula (I):-   wherein R¹ is NHOH, hydroxy, or lower alkyloxy;-   R² is hydrogen atom, optionally substituted lower alkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted heteroaryl, or optionally substituted heteroarylalkyl;-   R³ is hydrogen atom, optionally substituted lower alkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted heteroaryl, or optionally substituted heteroarylalkyl;-   R⁴ is optionally substituted arylene, or optionally substituted    heteroarylene;-   R⁵ is a bond, —(CH₂)p—, —CH═CH—, —C≡C—, —CO—, —CO—NH—, —N═N—,    —N(R^(A))—, —NH—CO—NH—, —NH—CO—, —O—, —S—, —SO₂—, —SO₂NH—,    —SO₂—NH—N═CH—, or-   a group represented by the formula:-   wherein R^(A) is hydrogen atom or lower alkyl, p is 1 or 2-   R⁶ is optionally substituted naphtyl, optionally substituted    isoquinolyl, optionally substituted quinolyl, optionally substituted    1,3-benzodioxolyl, optionally substituted benzofuranyl, or    optionally substituted benzothienyl, its optically active substance,    its prodrug, their pharmaceutically acceptable salt, or solvate    thereof.-   In more detail, the invention relates to the following 2)-23).-   2) A compound of the formula (II):-   wherein R¹, R², R³, R⁴ and R⁵ are as defined in 1);-   R⁷ is each independently hydrogen atom, halogen, lower alkyl,    cycloalkyl, lower alkenyl, lower alkynyl, lower alkyloxy, lower    alkenyloxy, lower alkylthio, halo(lower)alkyl, hydroxy, carboxy,    lower alkyloxycarbonyl, aminocarbonyl, acyl, nitro, cyano, or    optionally substituted amino;-   m is 0, 1, 2, or 3,-   its optically active substance, its prodrug, their pharmaceutically    acceptable salt, or solvate thereof.-   3) A compound of the formula (III):-   wherein R¹, R³, R⁴, and R⁵ are as defined in 1);-   R⁷ and m are as defined in 2);-   R⁸ is hydrogen atom, lower alkyl optionally substituted with    aminocarbonyl or lower alkylthio, aryl optionally substituted with    hydroxy, aralkyl optionally substituted with hydroxy, or    heteroarylalkyl optionally substituted with hydroxy,-   its optically active substance, its prodrug, their pharmaceutically    acceptable salt, or solvate thereof.-   4) A compound, its optically active substance, its prodrug, their    pharmaceutically acceptable salt, or solvate thereof as described in    any one of 1) to 3), wherein R¹ is hydroxy.-   5) A compound, its optically active substance, its prodrug, their    pharmaceutically acceptable salt, or solvate thereof as described in    any one of 1) to 4), wherein R² and R⁸ are hydrogen atom, lower    alkyl optionally substituted with aminocarbonyl or lower alkylthio,    phenyl optionally substituted with hydroxy, benzyl optionally    substituted with hydroxy, or indol-3-ylmethyl optionally substituted    with hydroxy.-   6) A compound, its optically active substance, its prodrug, their    pharmaceutically acceptable salt, or solvate thereof as described in    any one of 1) to 5), wherein R² and R⁸ are hydrogen atom, methyl,    isopropyl, isobutyl, aminocarbonylmethyl, 2-methylthioethyl,    4-hydroxyphenyl, benzyl, 4-hydroxybenzyl, indol-3-ylmethyl, or    (5-hydroxy-indol-3-yl)methyl.-   7) A compound, its optically active substance, its prodrug, their    pharmaceutically acceptable salt, or solvate thereof as described in    any one of 1) to 6), wherein R³ is hydrogen atom.-   8) A compound, its optically active substance, its prodrug, their    pharmaceutically acceptable salt, or solvate thereof as described in    any one of 1) to 7), wherein R⁴ is 1,4-phenylene or    2,5-thiophen-diyl.-   9) A compound, its optically active substance, its prodrug, their    pharmaceutically acceptable salt, or solvate thereof as described in    any one of 1) to 8), wherein R⁵ is —C≡C—, —CO—NH—, —NH—CO—, —O—, or-   a group represented by a formula:    -   10) A compound of the formula (IV):-   wherein R⁹ is hydrogen atom, methyl, isopropyl, isobutyl,    aminocarbonylmethyl, 2-methylthioethyl, 4-hydroxyphenyl, benzyl,    4-hydroxybenzyl, indol-3-ylmethyl, or (5-hydroxy-indol-3-yl)methyl;-   R¹⁰ is 1,4-phenylene or 2,5-thiophen-diyl;-   R¹¹ is —C≡C—, —CO—NH—, —NH—CO—, —O—, or-   a group represented by a formula:-   R¹² is each independently hydrogen atom, halogen, lower alkyl, lower    alkyloxy, halo(lower)alkyl, nitro, cyano, optionally substituted    amino, or hydroxy;-   m is 0, 1, 2, or 3,-   its optically active substance, its prodrug, their pharmaceutically    acceptable salt, or solvate thereof.-   11) A pharmaceutical composition containing a compound of any one    of 1) to 10) as an active ingredient.-   12) A composition for inhibiting metalloproteinase containing a    compound of any one of 1) to 10) as an active ingredient.-   13) A composition for inhibiting matrix metalloproteinase containing    a compound of any one of 1) to 10) as an active ingredient.-   14) A composition for inhibiting matrix metalloproteinase-12    containing a compound of any one of 1) to 10) as an active    ingredient.-   15) A composition for treating or preventing chronic obstructive    pulmonary disease which contains as an active ingredient a compound    of any one of 1) to 10).-   16) Use of a compound of any one of 1) to 10) for preparation of a    pharmaceutical composition for treating chronic obstructive    pulmonary disease.-   17) A method for treating a mammal, including a human, to alleviate    the pathological effects of chronic obstructive pulmonary disease,    which comprises administration to said mammal of a compound as    described in any one of 1) to 10) in a pharmaceutically effective    amount.-   18) A method of inhibiting MMP-12, which is characterized by    contacting a compound as described in any one of 1) to 10) with    MMP-12.-   19) A pharmaceutical composition containing as an active ingredient    a compound having an inhibitory activity against matrix    metalloproteinase-12.-   20) A composition for treating or preventing chronic obstructive    pulmonary disease containing as an active ingredient a compound    having an inhibitory activity against matrix metalloproteinase-12.-   21) A method for treating a mammal, including a human, to alleviate    the pathological effects of chronic obstructive pulmonary disease,    which comprises administration to said mammal of a compound having    an inhibitory activity against matrix metalloproteinase-12.-   22) Use of a compound having an inhibitory activity against matrix    metalloproteinase-12 for preparation of a pharmaceutical composition    for treating chronic obstructive pulmonary disease.-   23) A method of inhibiting matrix metalloproteinase-12, which is    characterized by contacting a compound having an inhibitory activity    against matrix metalloproteinase-12 with matrix    metalloproteinase-12.

In the present specification, the term “lower alkyl” employed alone orin combination with other terms means a straight- or branched chainmonovalent hydrocarbon group having 1 to 8 carbon atom(s). Examples ofthe alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl,isohexyl, n-heptyl, n-octyl and the like. C1 to C6 alkyl is preferred.C1 to C3 alkyl is more preferred.

The term “lower alkenyl” employed alone or in combination with otherterms in the present specification means a straight- or branched chainmonovalent hydrocarbon group having 2 to 8 carbon atoms and at least onedouble bond. Examples of the alkenyl include vinyl, allyl, propenyl,crotonyl, isopentenyl, a variety of butenyl isomers and the like. C2 toC6 alkenyl is preferred. C2 to C4 alkenyl is more preferred.

The term “lower alkynyl” used in the present specification means astraight- or branched chain monovalent hydrocarbon group having 2 to 8carbon atoms and at least one triple bond. The alkynyl may contain (a)double bond(s). Examples of the alkynyl include ethynyl, 2-propynyl,3-butynyl, 4-pentynyl, 5-hexynyl, 6-heptynyl, 7-octynyl and the like. C2to C6 alkynyl is preferred. C2 to C4 alkynyl is more preferred.

The term “cycloalkyl ” used in the present specification includescycloalkyl group having 3 to 8 carbon atoms. Examples of cycloalkylgroup include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl and the like. C3 to C6 cycloalkyl is preferred.

In the present specification, the term “aryl” employed alone or incombination with other terms includes monocyclic or condensed ringaromatic hydrocarbons. Examples include phenyl, 1-naphtyl, 2-naphtyl,anthryl, and the like.

Preferable is phenyl as “aryl” for R².

Preferable is phenyl as “aryl” for R³.

In the present specification, the term “naphtyl” includes 1-naphtyl and2-naphtyl.

The term “aralkyl” herein used means the above-mentioned “lower alkyl”substituted with one or more above-mentioned “aryl” at any possibleposition. Examples of the aralkyl are benzyl, phenylethyl (e.g.,2-phenethyl and the like), phenylpropyl (e.g., 3-phenylpropyl and thelike), naphthylmethyl (e.g., 1-naphthylmethyl and 2-naphthylmethyl andthe like), anthrylmethyl (e.g., 9-anthrylmethyl and the like), and thelike. Benzyl and phenylethyl are preferred.

In the present specification, the term “heteroaryl” employed alone or incombination with other terms includes a 5 to 6 membered aromaticheterocyclic group which contains one or more hetero atoms selected fromthe group consisting of oxygen, sulfur, and nitrogen atoms in the ringand may be fused with cycloalkyl, aryl, non-aromatic heterocyclic group,and other heteroaryl at any possible position. Examples of theheteroaryl are pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl),furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl 3-thienyl),imidazolyl (e.g., 2-imidazotyl, 4-imidazolyl), pyrazolyl (e.g.,1-pyrazolyl, 3-pyrazolyl), isothiazolyl (e.g., 3-isothiazolyl),isoxazolyl (e.g., 3-isoxazolyl), oxazolyl (e.g., 2-oxazolyl), thiazolyl(e.g., 2-thiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl),pyrazinyl (e.g., 2-pyrazinyl), pyrimidinyl (e.g., 3-pyridazinyl),tetrazolyl (e.g., 1H-tetrazolyl), oxadiazolyl (e.g., 1,3,4-oxadiazolyl),thiadiazolyl (e.g., 1,3,4-thiadiazolyl), indolizinyl (e.g.,2-indolizinyl, 6-indolizinyl), isoindolyl (2-isoindolyl), indolyl (e.g.,1-indolyl, 2-indolyl, 3-indolyl), indazolyl (e.g., 3-indazolyl), puriyl(e.g., 8-puriyl), quinolizinyl (e.g., 2-quinolizinyl), isoquinolyl(e.g., 3-isoquinolyl), quinolyl (e.g., 2-quinolyl, 5-quinolyl),phthalazinyl (e.g., 1-phthalazinyl), naphthyridlinyl (e.g.,2-naphthyridinyl), quinolanyl (2-quinolanyl), quinazolinyl (e.g.,2-quinazolinyl), cinnolinyl (e.g., 3-cinnolinyl), pteridinyl (e.g.,2-pteridinyl), carbazolyl (e.g., 2-carbazolyl, 3-carbazolyl),phenanthridinyl (e.g., 2-phenanthridinyl, 3-phenanthridinyl), acridinyl(e.g., 1-acridinyl, 2-acridinyl), dibenzofuranyl (e.g.,1-dibenzofuranyl, 2-dibenzofuranyl), benzimidazolyl (e.g.,2-benzimidazolyl), benzisoxazolyl (e.g., 3-benzisoxazolyl), benzoxazolyl(e.g., 2-benzoxazolyl), benzoxadiazolyl (e.g., 4-benzoxadiazolyl),benzisothiazolyl (e.g., 3-benzisothiazolyl), benzothiazolyl (e.g.,2-benzothiazolyl), benzofuryl (e.g., 3-benzofuryl), benzothienyl (e.g.,2-benzothienyl) and the like.

Preferable are indolyl, imidazolyl and the like as “heteroaryl” for R².

Preferable are pyridyl, thienyl, furyl, imidazolyl and the like as“heteroaryl” for R³.

The term “heteroarylalkyl” herein used includes the above mentioned“lower alkyl” substituted with at least one above-mentioned “heteroaryl”at any possible position. Examples of the heteroarylalkyl arethiazolylmethyl (e.g., 4-thiazolylmethyl), thiazolylethyl (e.g.,5-thiazolyl-2-ethyl), benzothiazolylmethyl (e.g.,(benzothiazol-2-yl)methyl), indolylmethyl (e.g., (indol-3-yl)methyl),imidazolylmethyl (e.g., 4-imidazolylmethyl), benzothiazolylmethyl (e.g.,2-benzothiazolylmethyl), indazolylmethyl (e.g., 1-indazolylmethyl),benzotriazolylmethyl (e.g., 1-benzotriazolylmethyl), benzoquinolylmethyl(e.g., 2-benzoquinolylmethyl), benzimidazolylmethyl (e.g.,2-benzimidazolylmethyl), pyridylmethyl (e.g., 4-pyridylmethyl), and thelike.

Examples as “heteroarylalkyl” for R² are indolylmethyl (e.g.,indol-3-ylmethyl) and imidazolylmethyl (imidazol-5-ylmethyl) and thelike

In the present specification, the term “non-aromatic heterocyclic group”includes a 5 to 7 membered non-aromatic ring which contains one or morehetero atoms selected from the group consisting of oxygen, sulfur, andnitrogen atoms in the ring and a condensed ring which are formed withtwo or more of the non-aromatic ring. Examples of the non-aromaticheterocyclic group are pyrrolidinyl (e.g., 1-pyrrolidinyl,2-pyrrolidinyl), pyrrolinyl (e.g., 3-pyrrolinyl), imidazolidinyl (e.g.,2-imidazolidinyl), imidazolinyl (e.g., imidazolinyl), pyrazolidinyl(e.g., 1-pyrazolidinyl, 2-pyrazolidinyl), pyrazolinyl (e.g.,pyrazolinyl), piperidinyl (piperidino, 2-piperidinyl), piperazinyl(e.g., 1-piperazinyl), indolynyl (e.g., 1-indolynyl), isoindolinyl(e.g., isoindolinyl), morpholinyl (e.g., morpholino, 3-morpholinyl),4H-[1,2,4]oxaziazole-5-one, 1,2,3,4-tetrahydro-[1,8]naphtylidine,1,3-benzodioxolyl and the like.

The term “arylene” herein used means a divalent group of theabove-mentioned “aryl”. Examples of the arylene are phenylene,naphthylene, and the like. Mentioned in more detail, it is exemplifiedby 1,2-phenylene, 1,3-phenylen, 1,4-phenylene, and the like. Preferable

The term “heteroarylene” herein used means a divalent group of theabove-mentioned “heteroaryl”. Examples of the heteroarylene arethionphene-diyl, furan-diyl, pyridine-diyl, and the like. Mentioned inmore detail, it is exemplified by 2,5-thionphene-diyl, 2,5-furan-diyl,and the like.

In the present specification, the term “acyl” employed alone or incombination with other terms includes alkylcarbonyl in which alkyl groupis the above-mentioned “lower alkyl” and arylcarbonyl in which arylgroup is the above-mentioned “aryl”. Examples of the acyl are acetyl,propionyl, benzoyl, and the like. “Lower alkyl” and “aryl” may besubstituted respectively with substituents mentioned below.

The term “halogen” herein used means fluoro, chloro, bromo, and iodo.Fluoro, chloro, and bromo are preferred.

The term “lower alkyloxy” herein used are methyloxy, ethyloxy,n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, terand the like. Methyloxy, ethyloxy, n-propyloxy, isopropyloxy andn-butyloxy are preferred.

The term “lower alkylthio” herein used are methylthio, ethylthio, andthe like.

The term “lower alkenyloxy” herein used are vinyloxy, aryloxy,propenyloxy, crotonyloxy, isopentenyloxy and the like.

The term “lower alkyloxycarbonyl” herein used are methyloxycarbonyl,ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, and thelike.

In the present specification, the term “halo(lower)alkyl” employed aloneor in combination with other terms includes the above-mentioned “loweralkyl” which is substituted with the above mentioned “halogen” at 1 to 8positions, preferably, at 1 to 5. Examples of the halo(lower)alkyl aretrifluoromethyl, trichloromethyl, difluoroethyl, trifluoroethyl,dichloroethyl, trichloroethyl, and the like. Preferable istrifluoromethyl.

Examples of the term “halo(lower)alkyloxy” herein used aretrifluoromethyloxy and the like.

Examples of the term “lower alkylsulfonyl” herein used aremethylsulfonyl, ethylsulfonyl and the like. Preferable ismethylsulfonyl.

Examples of the term “acyloxy” herein used are acetyloxy, propionyloxy,benzoyloxy and the like.

In the present specification, the term “optionally substituted amino”includes amino or amino substituted with one or two of the abovementioned “lower alkyl”, “aralkyl”, “heteroarylalkyl” or “acyl”.Examples of the optionally substituted amino are amino, methylamino,dimethylamino, ethylmethylamino, diethylamino, benzylamino, acetylamino,benzoylamino and the like. Preferable are amino, methylamino,dimethylamino, ethylmethylamino, diethylamino and acetylamino.

Examples of the term “optionally substituted aminocarbonyl” herein usedare aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl,ethylmethylaminocarbonyl, diethylaminocarbonyl and the like. Preferableis aminocarbonyl, diethylaminocarbonyl.

The substituents of “optionally substituted lower alkyl” are cycloalkyl,hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro,cyano, carboxy, lower alkyloxycarbonyl, halo(lower)alkyl,halo(lower)alkyloxy, optionally substituted amino, optionallysubstituted aminocarbonyl, acyl, acyloxy, optionally substitutednon-aromatic heterocyclic group, aryloxy (e.g., phenyloxy), aralkyloxy(e.g., benzyloxy), lower alkylsulfonyl, guanidino, azo group, optionallysubstituted ureide and the like. These substituents are able to locateat one or more of any possible positions.

Preferable are hydroxy, lower alkyloxy as substituents of “optionallysubstituted lower alkyl” for R².

Preferable are hydroxy, lower alkyloxy, optionally substitutednon-aromatic heterocyclic group as substituents of “optionallysubstituted lower alkyl” for R³.

The substituents of “optionally substituted naphtyl”, “optionallysubstituted isoquinolyl”, “optionally substituted quinolyl”, “optionallysubstituted 1,3-benzodioxolyl”, “optionally substituted benzofuranyl”,“optionally substituted benzothienyl”, “optionally substituted arylene”,“optionally substituted heteroarylene”, “optionally substituted aryl”,“optionally substituted heteroaryl”, “optionally substitutednon-aromatic heterocyclic group”, “optionally substituted aralkyl”,“optionally substituted heteroarylalkyl”, and “optionally substitutedureide” herein used are optionally substituted lower alkyl, cycloalkyl,lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, loweralkylthio, halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl,halo(lower)alkyl, halo(lower)alkyloxy, optionally substituted amino,optionally substituted aminocarbonyl, acyl, acyloxy, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted non-aromatic heterocyclic group, optionally substitutedaralkyl, lower alkylsulfonyl, guanidino group, azo group, or optionallysubstituted ureide and the like. These substituents are able to locateat one or more of any possible positions.

Preferable are halogen, nitro, cyano, lower alkyloxy, and the like inthe above-mentioned substituents as substituents for R⁴ of “optionallysubstituted arylene” and “optionally substituted heteroarylene”. Morepreferable are unsubstituted “arylene” and unsubstituted “heteroarylene”as “optionally substituted arylene” and “optionally substitutedheteroarylene”.

Preferable are optionally substituted lower alkyl, lower alkenyl, loweralkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen,nitro, cyano, carboxy, lower alkyloxycarbonyl, halo(lower)alkyl,halo(lower)alkyloxy, optionally substituted amino, optionallysubstituted aminocarbonyl, acyl, acyloxy and the like in theabove-mentioned substituents, as substituents for R² of “optionallysubstituted aryl”. More preferable are aryl optionally substituted withhydroxy as “optionally substituted aryl”.

Preferable are optionally substituted lower alkyl, lower alkenyl, loweralkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen,nitro, cyano, carboxy, lower alkyloxycarbonyl, halo(lower)alkyl,halo(lower)alkyloxy, optionally substituted amino, optionallysubstituted aminocarbonyl, acyl, acyloxy and the like in theabove-mentioned substituents, as substituents for R³ of “optionallysubstituted aryl”. More preferable are aryl optionally substituted withhydroxy, lower alkyloxy, halogen, or halo(lower)alkyl as “optionallysubstituted aryl”.

Preferable are optionally substituted lower alkyl, lower alkenyl, loweralkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen,nitro, cyano, carboxy, lower alkyloxycarbonyl, halo(lower)alkyl,halo(lower)alkyloxy, optionally substituted amino, optionallysubstituted aminocarbonyl, acyl, acyloxy and the like in theabove-mentioned substituents, as substituents for R² of “optionallysubstituted heteroaryl”. More preferable are heteroaryl optionallysubstituted with hydroxy or halogen as “optionally substitutedheteroaryl”.

Preferable are optionally substituted lower alkyl, lower alkenyl, loweralkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen,nitro, cyano, carboxy, lower alkyloxycarbonyl, halo(lower)alkyl,halo(lower)alkyloxy, optionally substituted amino, optionallysubstituted aminocarbonyl, acyl, acyloxy and the like in theabove-mentioned substituents, as substituents for R³ of “optionallysubstituted heteroaryl”. More preferable are heteroaryl optionallysubstituted with hydroxy, lower alkyloxy, halogen, or halo(lower)alkyl,as “optionally substituted heteroaryl”.

Preferable are optionally substituted lower alkyl, lower alkenyl, loweralkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen,nitro, cyano, carboxy, lower alkyloxycarbonyl, halo(lower)alkyl,halo(lower)alkyloxy, optionally substituted amino, optionallysubstituted aminocarbonyl, acyl, acyloxy and the like in theabove-mentioned substituents, as substituents for R² of “optionallysubstituted aralkyl”. More preferable are aralkyl optionally substitutedwith hydroxy as “optionally substituted aralkyl”.

Preferable are optionally substituted lower alkyl, lower alkenyl, loweralkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen,nitro, cyano, carboxy, lower alkyloxycarbonyl, halo(lower)alkyl,halo(lower)alkyloxy, optionally substituted amino, optionallysubstituted aminocarbonyl, acyl, acyloxy and the like in theabove-mentioned substituents, as substituents for R³ of “optionallysubstituted aralkyl”. More preferable are aralkyl optionally substitutedwith hydroxy, lower alkyloxy, halogen, or halo(lower)alkyl as“optionally substituted aralkyl”.

Preferable are optionally substituted lower alkyl, lower alkenyl, loweralkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen,nitro, cyano, carboxy, lower alkyloxycarbonyl, halo(lower)alkyl,halo(lower)alkyloxy, optionally substituted amino, optionallysubstituted aminocarbonyl, acyl, acyloxy and the like in theabove-mentioned substituents, as substituents for R² of “optionallysubstituted heteroarylalkyl”. More preferable are heteroarylalkyloptionally substituted with halogen or hydroxy as “optionallysubstituted heteroarylalkyl”.

Preferable are optionally substituted lower alkyl, lower alkenyl, loweralkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen,nitro, cyano, carboxy, lower alkyloxycarbonyl, halo(lower)alkyl,halo(lower)alkyloxy, optionally substituted amino, optionallysubstituted aminocarbonyl, acyl, acyloxy and the like in theabove-mentioned substituents, as substituents for R³ of “optionallysubstituted heteroarylalkyl”. More preferable are heteroarylalkyloptionally substituted with hydroxy, lower alkyloxy, halogen, orhalo(lower)alkyl as “optionally substituted heteroarylalkyl”.

Preferable are optionally substituted lower alkyl, cycloalkyl, loweralkenyl, lower alkynyl, hydroxy, lower alkyloxy, lower alkenyloxy,mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, loweralkyloxycarbonyl, halo(lower)alkyl, halo(lower)alkyloxy, optionallysubstituted amino, optionally substituted aminocarbonyl, acyl, acyloxyand the like, as substituents of “optionally substituted naphtyl”,“optionally substituted isoquinolyl”, “optionally substituted quinolyl”,“optionally substituted 1,3-benzodioxolyl”, “optionally substitutedbenzofuranyl”, “optionally substituted benzothienyl”. More preferableare halogen, lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl,lower alkyloxy, lower alkenyloxy, lower alkylthio, halo(lower)alkyl,hydroxy, carboxy, lower alkyloxycarbonyl, aminocarbonyl, acyl, nitro,cyano, or optionally substituted amino as substituent. Much morepreferable are lower alkyl, lower alkyloxy, halogen, lower alkylthio oroptionally substituted amino.

BEST MODE FOR CARRYING OUT THE INVENTION

Compounds (I) of the present invention are able to be synthesized inaccordance with the procedure described in WO97/27174 (Method A to F)and WO99/04780.

The term “compound of the present invention” herein used includes apharmaceutically acceptable salt or its solvate. The salt is exemplifiedby a salt with alkali metals (e.g., lithium, sodium, potassium, and thelike), alkaline earth metals (e.g., magnesium, calcium, and the like),ammonium, organic bases, amino acids, mineral acids (e.g., hydrochloricacid, hydrobromic acid, phosphoric acid, sulfuric acid, and the like),or organic acids (e.g., acetic acid, citric acid, maleic acid, fumaricacid, benzenesulfonic acid, p-toluenesulfonic acid, and the like) or bya solvate with an appropriate solvent. These salts and solvates can beformed by the usual method. Preferable are hydrates as a solvates. Thesehydrates can coordinate with any water molecules.

The present invention includes prodrugs of compounds of the presentinvention. Prodrug is a derivative of the compound having a group whichcan be decomposed chemically or metabolically, and such prodrug is acompound according to the present invention which becomespharmaceutically active by means of solvolysis or by placing thecompound in vivo under a physiological condition. The method of bothselection and manufacture of appropriate prodrug derivatives isdescribed in, for example. Design of Prodrugs, Elsevier, Amsterdam,1985. For instance, prodrugs such as an ester derivative, optionallysubstituted alkyloxycarbonyl, which is prepared by reacting a basal acidcompound with a suitable alcohol, or an amide derivative, optionallysubstituted alkylaminocarbonyl, which is prepared by reacting a basalacid compound with a suitable amine are exemplified when the compoundsaccording to present invention have a carboxylic group. Particularlypreferred esters as prodrugs are methyl ester, ethyl ester, n-propylester, isopropyl ester, n-butyl ester, isobutyl ester, tert-butyl ester,morpholinoethyl ester, and N,N-diethylglycolamido ester, and the like.For instance, prodrugs such as an acyloxy derivative which is preparedby reacting a basal hydroxy compound with a suitable acyl halide or asuitable acid anhydride are exemplified when the compounds according topresent invention have a hydroxy group. Particularly preferred acyloxyderivatives as prodrugs —OCOC₂H₅, —OCO(t-Bu), —OCOC₁₅H₃,—OCO(m-COONa—Ph), —OCOCH₂CH₂COONa, —OCOCH(NH₂)CH₃, —OCOCH₂N(CH₃)₂, andthe like. For instance, prodrugs such as an amide derivative which isprepared by reacting a basal amino compound with a suitable acid halideor a suitable acid anhydride are exemplified when the compoundsaccording to present invention have an amino group. Particularlypreferred amide as prodrugs are —NHCO(CH₂)₂₀CH₃, —NHCOCH(NH₂)CH₃, andthe like.

The compound of the present invention is not restricted to anyparticular isomers but includes all possible isomers and racemicmodifications.

The compound of the present invention has an excellent activity againstinhibiting MMP-12, as described in the following test example.

Definitely, the compounds of the present invention are useful in thetreatment of diseases such as chronic obstructive pulmonary disease,osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontaldisease, advanced virus infection (e.g., HIV infection),arteriosclerosis obliterans, arteriosclerotic aneurysm, atherosclerosis,restenosis, sepsis, septic shock, coronary thrombosis, aberrantangiogenesis, scleritis, multiple sclerosis, open angle glaucoma,retinopathies, proliferative retinopathy, neovascular glaucoma,pterygium, keratitis, epidermolysis bullosa, psoriasis, diabetes,nephritis, neurodegengerative disease, inflammation, osteoporosis,deossification, gingivitis, tumor growth, tumor angiogenesis, oculartumor, angiofibroma, hemangioma, fever, hemorrhage, coagulation,cachexia, anorexia, acute infection, shock, autoimmune disease, malaria,Crohn disease, meningitis, heart failure, asthmatic respiratory tractdisease, arteriosclerosis, and gastric ulcer. The compounds are expectedespecially as compositions of treating for chronic obstructive pulmonarydisease.

When the compound of the present invention is administered to a personfor the treatment of the above diseases, it can be administered orallyas powder, granules, tablets, capsules, pilulae, and liquid medicines,or parenterally as injections, suppositories, percutaneous formulations,insufflation, or the like. An effective dose of the compound isformulated by being mixed with appropriate medicinal admixtures such asexcipient, binder, penetrant, disintegrators, lubricant, and the like ifnecessary. Parenteral injections are prepared by sterilizing thecompound together with an appropriate carrier.

The dosage varies with the conditions of the patients, administrationroute, their age, and body weight. In the case of oral administration,the dosage can generally be between 0.1 to 100 mg/kg/day, and preferably0.1 to 20 mg/kg/day for adult.

The following examples are provided to further illustrate the presentinvention and are not to be constructed as limiting the scope thereof.

Abbreviations described below are used in the following examples.

-   Me: methyl-   Et: ethyl-   n-Pr: n-propyl-   i-Pr: isopropyl-   n-Bu: n-butyl-   i-Bu: isobutyl-   t-Bu: tert-butyl-   Ph: phenyl-   Bn: benzyl-   Indol-3-yl methyl: indol-3-ylmethyl-   DMSO: dimethyl sulfoxide

EXAMPLE Example 1 The Preparation of the Compound (A-1)

(Process 1)

To a suspension of L-valine methyl ester hydrochloride (1) (3.30 g, 19.7mmol), and N-methylmorpholine (5.7 ml, 51.8 mmol) in tetrahydrofuran(100 ml) was added in an ice bath 4-iodobenzenesulfonyl chloride (2)(5.00 g, 16.5 mmol). After the mixture was stirred at 0° C. for 0.5 hand then at room temperature for 2.5 h, the reaction mixture was pouredinto ice-2mol/L hydrochloric acid and was extracted with ethyl acetate.The organic layer was successively washed with saturated sodiumhydrogencarbonate aqueous solution and brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue wascrystallized from ethyl acetate-hexane to obtain the product (3) (4.32g, yield: 65.8%) with a melting point of 99-102° C.

IR(KBr, v max cm⁻¹) 3271, 1740, 1568, 1346, 1161

¹H NMR (CDCl₃,δppm): 0.87 (d, J=6.6 Hz, 3H), 0.96 (d, J=6.8 Hz, 3H),2.07 (m, 1H), 3.49 (s, 3H), 3.74 (m, 1H), 5.10 (d, J=10.4 Hz, 1H), 7.54(d, J=8.8 Hz, 2H), 7.86 (d, J=8.4 Hz, 2H)

[α]_(D)+6.7±0.9 (c=0.509, DMSO, 24° C.)

Elemental analysis (C₁₂H_(16/)NO₄SI.0.1H₂O)

Calcd.: C;36.12, H;4.09, N;3.51, S;8.04, I;31.80

Found: C;36.32, H;4.08, N;3.58, S;7.97, I;31.57

(Process 2)

To a solution of compound (3) (1.00 g, 2.52 mmol) in dimethyl-formamide(6 ml) was added 2-ethynylnaphthalene the mixture was degassed underargon atmosphere. Bis(triphenylphosphine)-palladium (II) dichloride(44.0 mg, 62.7 μmol), copper iodide (I) (24.0 mg, 0.126 μmol) andtriethylamine (1.05 ml, 7.56 mmol) were added to it and then the mixturewas degassed under argon atmosphere again. After the reaction mixturewas stirred at 50° C. for 15 h, it was poured into ice-2mol/Lhydrochloric acid and was extracted with ethyl acetate. The organiclayer was washed successively with 5% saturated sodium hydrogencarbonateaqueous solution and brine, dried over anhydrous sodium sulfate andevaporated under reduced pressure. The residue was subjected to silicagel column chromatography and the fraction eluted with hexane/ethylacetate/chloroform=3/1/1 to 2/1/1 was collected, recrystallized fromacetone/n-hexane to yield the product (4) (848 mg, yield: 80.0%) with amelting point of 152-154° C.

IR (KBr, v max cm⁻¹) 3288, 2216, 1736, 1597, 1348, 1169

¹H NMR (CDCl₃, δppm): 0.89 (d, J=6.9 Hz, 3H), 0.98 (d, J=6.6 Hz, 3H),2.06 (m, 1H), 3.50 (s, 3N), 3.73 (m, 1H), 5.12 (d, J=10.2 Hz, 1H),7.51-7.60 (m, 3H), 7.67 (d, J=8.7 Hz, 2H), 7.81-7.85 (m, 5H), 8.08 (s,1H)

[α]_(D)−5.7±0.9 (c=0.504, DMSO, 24° C.)

Elemental analysis (C₂₄H₂₃NO₄S)

Calcd.: C;68.39, H;5.50, N;3.32, S;7.61

Found: C;68.32, H;5.47, N;3.41, S;7.38

(Process 3)

To a solution of compound (4) (818 mg, 1.94 mmol) in dimethylsulfoxide(16.4 ml) was added at room temperature 1 mol/L aqueous sodium hydroxidesolution (5.80 ml, 5.82 mmol). The solution was stirred at 60° C. for 15h and poured into ice-2 mol/L hydrochloric acid. The mixture wasextracted with ethyl acetate and the organic layer was washed withbrine, dried over anhydrous sodium sulfate and evaporated under reducedpressure. The residue was crystallized from acetone-water to give theproduct (A-1) (763 mg, yield: 96.5%) with a melting point of 171-173° C.

IR (KBr, v max cm⁻¹) 3336, 2214, 1709, 1346, 1167

¹H NMR (DMSO-d₆, δppm): 0.82 (d, J=6.6 Hz, 3H), 0.84 (d, J=6.6 Hz, 3H),1.97 (m, 1H), 3.73 (br s, 1H), 7.58-7.67 (m, 3H), 7.76 (d, J=8.4 Hz,2H), 7.83 (d, J=8.7 Hz, 2H), 7.90-8.01 (m, 3H), 8.15 (d, J=9.0 Hz, 1H),8.25 (s, 1H), 12.70 (br s, 1H)

[α]_(D)+11.4 ±1.0 (c=0.511, DMSO, 24° C.)

Elemental analysis (C₂₃H₂₁NO₄S.0.3H₂O)

Calcd.: C;66.91, H;5.27, N;3.39, S;7.77

Found: C;66.84, H;5.28, N;3.41, S;7.66

The following compound (A-2) to compound (A-30), compound (B-1) tocompound (B-29), compound (C-1) to compound (C-2), compound (D-1) tocompound (D-2), compound (E-1) to compound (E-10), compound (F-1) tocompound (F-2), and compound (G-1) were synthesized in a manner similarto Example 1.

Their results were shown in tables 1 to 5, tables 6 to 9, table 10,table 11, table 12 to 13, table 14, and table 15.

TABLE 1

Example Compound No. No. R² R⁶ * ¹H-NMR (DMSO-d₆) 2 A-2 Bn

R 2.74(dd, J=9.2, 13.6Hz, 1H), 2.98(dd, J=5.2, 13.6Hz, 1H), 3.91(m, 1H),7.13-7.28(m, 5H), 7.55-7.65(m, 7H), 7.93-8.04(m, 3H), 8.26(s, 1H),8.44(d, J=9.0Hz, 1H), 12.80(brs, 1H) 3 A-3 Bn

S 2.75(dd, J=9.3, 13.5Hz, 1H), 2.98(dd, J=5.4, 14.1Hz, 1H), 3.93(m, 1H),7.10-7.23(m, 5H), 7.55-7.67(m, 7H), 7.96-8.01(m, 3H), 8.25(s, 1H),8.42(d, J=9.0Hz, 1H), 12.00(brs, 1H) 4 A-4 (4-OH- indole- 3- yl)methyl

R 2.79(dd, J=8.4, 14.4Hz, 1H), 2.99(dd, J=6.0, 14.4Hz, 1H), 3.95(m, 1H),6.59(dd, J=2.4, 8.7Hz, 1H), 6.72(d, J=2.4Hz, 1H), 6.98(d, J=2.4Hz, 1H),7.11(d, J=8.7Hz, 1H), 7.50- 7.70(m, 7H), 7.90-8.10(m, 3H), 8.24(s, 1H),8.34(d, J=8.1Hz, 1H), 8.59(s, 1H), 10.50(s, 1H), 12.65(br s, 1H) 5 A-5i-Pr

R 0.81(d, J=6.9Hz, 3H), 0.84(d, J= 6.9Hz, 3H), 1.97(m, 1H), 3.55(s, 1H),7.57-7.63(m, 2H), 7.58-7.67(m, 3H), 7.76(d, J=8.4Hz, 2H), 7.83(d, J=9.0Hz, 2H), 7.95-8.01(m, 3H), 8.13(s, 1H), 8.25(s, 1H), 12.4-12.8(brs,1H) 6 A-6 i-Pr

S 0.81(d, J=6.9Hz, 3H), 0.84(d, J= 6.9Hz, 3H), 1.97(m, 1H), 3.48(br, s,1H), 7.58-7.67(m, 3H), 7.76(d, J= 8.4Hz, 2H), 7.83(d, J=8.7Hz, 2H),7.90- 8.01(m, 3H), 8.15(d, J=9.0Hz, 1H), 8.25(s, 6H), 12.60-12.80(brs,1H) 7 A-7 Me

R 1.19(d, J=7.4Hz, 3H), 3.83(m, 1H), 7.54-7.70(3H), 7.78(d, J= 8.2Hz,2H), 7.85(d, J=8.8Hz, 2H) 7.92-8.06(m, 3H), 8.25(s, 1H), 8.16(brs, 1H),12.65(brs, 1H) 8 A-8 Me

S 1.19(d, J=7.4Hz, 3H), 3.83(m, 1H), 7.54-7.70(3H), 7.78(d, J= 8.2Hz,2H), 7.85(d, J=8.8Hz, 2H) 7.92-8.06(m, 3H), 8.25(s, 1H), 8.31(brs, 1H),12.70(brs, 1H)

TABLE 2 Example Compound No. No. R² R⁶ * ¹H-NMR (DMSO-d₆) 9 A-9  H

3.65(d, J=4.8Hz, 2H), 7.66-7.69(3H), 7.78(d, J=8.4Hz, 2H), 7.86(d, J=8.8Hz, 2H), 7.92-8.04(m, 3H), 8.19(m, 1H), 8.25(s, 1H), 12.70(brs, 1H)10 A-10 i-Bu

R 0.74(d, J=6.2Hz, 3H), 0.83(d, J= 6.2Hz, 3H), 1.41(t, J=6.6Hz, 2H),1.60(m, 1H), 3.65(m, 1H), 7.56-7.70(m, 3H), 7.77(d, J=8.4Hz, 2H),7.83(d, J=8.4Hz, 2H), 7.92-8.04(m, 4H), 8.10(br, 1H), 8.26(s, 1H) 11A-11 i-Bu

S 0.73(d, J=6.6Hz, 3H), 0.83(d, J= 6.6Hz, 3H), 1.38-1.45(m, 2H), 1.60(m,1H), 3.70(m, 1H), 7.56-7.70(m, 3H), 7.77(d, J=8.4Hz, 2H), 7.83(d, J=8.4Hz, 2H), .7.94-8.04(m, 3H), 8.26(s, 1H), 8.30(br s, 1H), 12.70(br,1H) 12 A-12 4-OH— Ph

R 4.78(s, 1H), 6.64(d, J=8.8Hz, 2H), 7.07(d, J=8.8Hz, 1H), 7.55-7.64(m,3H), 7.68(d, J=8.8Hz, 2H), 7.77(d, J=8.8Hz, 2H), 7.93-8.04(m, 3H),8.25(s, 1H), 8.65(br, 1H), 9.45(brs, 1H) 13 A-13 4-OH— Bn

R 2.68(dd, J=7.4, 14.0Hz, 1H), 2.85(dd, J=5.8, 14.0Hz, 1H), 3.72(m, 1H),6.61(d, J=8.4Hz, 2H), 6.95(d, J=8.4Hz, 2H), 7.55-7.70(m, 7H),7.92-8.04(m, 3H), 8.25(s, 1H), 9.20(br, 1H) 14 A-14 Indole- 3- ylmethyl

R 2.89(dd, J=8.0, 14.5Hz, 1H), 3.09(dd, J=5.4, 14.5Hz, 1H), 3.94(m, 1H),6.90-7.10(m, 3H), 7.27-7.40(m, 2H), 7.52-7.70(m, 7H), 7.92-8.03(m, 3H),8.25(s, 1H), 8.32(m, 1H), 10.81(s, 1H) 15 A-15 Indole- 3- ylmethyl

S 2.89(dd, J=8.6, 14.2Hz, 1H), 3.09(dd, J=6.2, 14.2Hz, 1H), 3.95(m, 1H),6.91-7.14(m, 3H), 7.30-7.38(m, 2H), 7.52-7.67(m, 7H), 7.94-8.06(m, 3H),8.25(s, 1H), 8.37(m, 1H), 10.82(s, 1H), 12.71(br, 1H) 16 A-16MeS—CH₂—CH₂—

R 1.60-2.00(m, 2H), 1.96(s, 3H), 2.30- 2.50(m, 2H), 3.91(s, 1H), 7.50-7.70(m, 3H), 7.78(d, J=8.4Hz, 2H), 7.83(d, J=8.4Hz, 2H), 7.90-8.10(m,3H), 8.25(s, 1H), 8.33(d, J=8.1Hz, 1H), 12.75(br s, 1H).

TABLE 3 Example Compound No. No. R² R⁶ * ¹H-NMR (DMSO-d₆) 17 A-17MeS—CH₂—CH₂—

R 1.71-1.88(m, 2H), 1.96(s, 3H), 2.25- 2.46(m, 2H) 3.91(s, 1H),7.57-7.68(m, 3H), 7.77(d, J=8.8Hz, 2H), 7.83(d, J=8.8Hz, 2H),7.96-8.02(m, 3H), 8.26(s, 1H), 8.34(d, J=8.8Hz, 1H), 12.80(brs, 1H) 18A-18 HOOC—CH₂—

R 2.46(dd, J=7.2, 16.5Hz, 1H), 2.63(dd, J=6.6, 16.5Hz, 1H), 4.11(m, 1H),7.56- 7.64(m, 2H), 7.66(dd, J=1.8, 8.4Hz, 1H), 7.77(d, J=8.4Hz, 2H),7.84(d, J=8.4Hz, 2H), 7.94-8.03(m, 3H), 8.26(s, 1H), 8.38(br s, 1H),12.67(br s, 2H) 19 A-19 HOOC—CH₂—

S 2.46(dd, J=7.2, 16.5Hz, 1H), 2.63 (dd, J=6.6, 16.5Hz, 1H), 4.11(m,1H), 7.57-7.64(m, 2H), 7.66(dd, J=1.5, 8.4Hz, 1H), 7.77(d, J=8.7Hz, 2H),7.84(d, J=8.7Hz, 2H), 7.94- 8.03(m, 3H), 8.26(s, 1H), 8.38(br s, 1H),12.69(br s, 2H) 20 A-20 HO—CH₂—

R 3.52(dd, J=6.0, 11.1Hz, 1H), 3.56 (dd, J=5.4, 11.1Hz, 1H), 3.82(dt,J=8.7, 5.4Hz, 1H), 5.10(br s, 1H), 7.56-7.64(m, 2H), 7.65(dd, J=1.5,8.4Hz, 1H), 7.77(d, J=8.4Hz, 2H), 7.86(d, J=8.4Hz, 2H), 7.94-8.03(m,3H), 8.20(d, J=9.0Hz, 1H), 8.26(s, 1H), 12.57(br s, 1H) 21 A-21 Bn

R 2.37(dd, J=9.2, 13.8Hz, 1H), 2.96 (dd, J=5.9, 13.4Hz, 1H), 3.90(m,1H), 5.10(s, 2H), 7.00(d, J=8.8Hz, 1H), 7.05-7.25(7H), 7.56(s, 4H),8.39(d, J=9.2Hz, 1H), 12.75(br s, 1H) 22 A-22 Bn

S 2.37(dd, J=9.2, 13.8Hz, 1H), 2.96 (dd, J=5.9, 13.4Hz, 1H), 3.90(m,1H), 5.10(s, 2H), 7.00(d, J=8.8Hz, 1H), 7.05-7.25(7H), 7.56(s, 4H),8.39(d, J=9.2Hz, 1H), 12.75(br s, 1H) 23 A-23 Me

R 1.17(d, J=7.2Hz, 3H), 3.80(q, J= 8.4Hz, 1H), 6.10(s, 2H), 7.00(dd, J=1.2, 5.7Hz, 1H), 7.13-7.15(m, 2H), 7.68(d, J=6.9Hz, 2H), 7.79(d, J=6.9Hz, 2H), 8.26(d, J=8.4Hz, 1H), 12.66(br, 1H)

TABLE 4 Example Compound No. No. R² R⁶ * ¹H-NMR (DMSO-d₆) 24 A-24 Me

S 1.17(d, J=7.2Hz, 3H), 3.80(m, 1H), 6.10(s, 2H), 7.00(d, J=5.7Hz, 1H),7.13-7.15(m, 2H), 7.68(d, J=6.9Hz, 2H), 7.79(d, J=6.9Hz, 2H), 8.30(m,1H), 12.60(br, 1H) 25 A-25 i-Pr

R 0.80(d, J=6.3Hz, 3H), 0.83(d, J=6.3Hz, 3H), 1.93(m, 1H), 3.53(m, 1H),6.10(s, 2H), 7.00(d, J=8.4Hz, 1H), 7.13(d, J=8.4Hz, 1H), 7.15(s, 1H),7.66(d, J=8.7Hz, 2H), 7.78(d, J=8.7Hz, 2H), 8.11(m, 1H), 12.60(brs, 1H)26 A-26 i-Pr

S 0.80(d, J=6.6Hz, 3H), 0.83(d, J= 6.6Hz, 3H), 1.93(m, 1H), 3.53(m, 1H),6.10(s, 2H), 6.99(d, J=7.5Hz, 1H), 7.14(d, J=7.5Hz, 1H), 7.15(s, 1H),7.66(d, J=8.1Hz, 2H), 7.78(d, J= 8.1Hz, 2H), 8.11(m, 1H), 12.62(br, 1H)27 A-27 H

3.62(d, J=4.5Hz, 2H), 6.10(s, 2H), 7.00(m, 1H), 7.12-7.15(m, 2H), 7.67-7.70(m, 2H), 7.80(d, J=8.7Hz, 2H), 8.16(m, 1H), 12.71(brs, 1H) 28 A-28MeS—CH₂—CH₂—

R 1.63-1.90(m, 2H), 1.95(s, 1H), 2.26- 2.45(m, 2H), 3.87(m, 1H), 6.10(s,2H), 7.00(d, J=7.8Hz, 2H), 7.12- 7.15(m, 2H), 7.68(d, J=8.4Hz, 2H),7.78(d, J=8.4Hz, 2H), 8.32(d, J=8.7Hz, 1H), 12.78(br, 1H) 29 A-29 i-Pr

R 0.79(d, J=6.9Hz, 3H), 0.83(d, J= 6.9Hz, 3H), 1.94(m, 1H), 3.52(m, 1H),4.24-4.33(m, 4H), 6.92(d, J=8.1Hz, 1H), 7.04-7.12(m, 2H), 7.66(d, J=8.7Hz, 2H), 7.77(d, J=8.7Hz, 2H), 8.14(d, J=9.3Hz, 1H), 12.66(br s, 1H)30 A-30 i-Pr

S 0.79(d, J=6.6Hz, 3H), 0.83(d, J=6.9Hz, 3H), 1.95(m, 1H), 3.53(m, 1H),4.20-4.40(m, 4H), 6.93(d, J=7.8Hz, 1H), 7.05-7.14(m, 2H), 7.67(d,J=8.1Hz, 2H), 7.78(d, J=8.1Hz, 2H), 8.17(d, J=8.7Hz, 1H), 12.67(br s,1H) 31 A-31 Bn

R 2.73(dd, J=9.3, 13.5Hz, 1H), 2.96(dd, J=5.4, 13.5Hz, 1H), 3.90(m, 1H),6.92(dd, J=0.6, 8.1Hz, 1H), 7.04- 7.27(m, 7H), 7.50-7.60(m, 4H), 8.40(d,J=9.3Hz, 1H), 12.77(br s, 1H)

TABLE 5 Example Compound No. No. R² R⁶ * ¹H-NMR (DMSO-d₆) 32 A-32 Bn

R 2.74(dd, J=9.3, 13.5Hz, 1H), 2.97(dd, J=5.4, 13.5Hz, 1H), 3.90(s, 3H),3.92(m, 1H), 7.13-7.27(m, 6H), 7.39(d, J= 2.7Hz, 1H), 7.57-7.64(m, 5H),7.89(dd, J=4.5, 9.0Hz, 2H), 8.17(s, 1H), 8.45(d, J=8.7Hz, 1H), 12.83(brs, 1H) 33 A-33 Bn

S 2.74(dd, J=9.3, 13.5Hz, 1H), 2.98(dd, J=5.4, 13.5Hz, 1H), 3.91(s, 3H),3.92(m, 1H), 7.12-7.27(m, 6H), 7.39(d, J= 2.4Hz, 1H), 7.57-7.65(m, 5H),7.89(dd, J=4.5, 8.7Hz, 2H), 8.17(s, 1H), 8.44(d, J=9.0Hz, 1H), 12.81(brs, 1H) 34 A-34 i-Pr

R 0.81(d, J=6.6Hz, 3H), 0.84(d, J=6.9Hz, 3H), 1.96(m, 1H), 3.55(m, 1H),3.90(s, 3H), 7.24(dd, J=2.7, 9.0Hz, 1H), 7.39(d, J=2.1Hz, 1H), 7.60(dd,J=1.5, 8.7Hz, 1H), 7.73(d, J=8.4Hz, 2H), 7.81(d, J=8.4Hz, 2H), 7.88(dd,J=3.3, 9.0Hz, 2H), 8.16(s, 1H), 8.19(br s, 1H), 12.75(br s, 1H) 35 A-35Me

R 1.18(d, J=7.2Hz, 3H), 3.82(m, 1H), 3.90(s, 3H), 7.24(dd, J=2.4, 9.0Hz,1H), 7.39(d, J=2.4Hz, 1H), 7.60(dd, J=1.8, 8.7Hz, 1H), 7.75(d, J=8.4Hz,2H), 7.82(d, J=8.7Hz, 2H), 7.89(dd, J=3.9, 9.3Hz, 2H), 8.16(s, 1H),8.29(d, J=7.8Hz, 1H), 12.75(br s, 1H)

TABLE 6

Example Compound No. No. R² R⁶ * ¹H-NMR (DMSO-d₆) 31 B-1 Bn

R 2.77(dd, J=9.6, 13.8Hz, 1H), 3.02(d, J=5.1, 13.8Hz, 1H), 3.98(m, 1H),7.16-7.27(m, 5H), 7.28(d, J=3.9Hz, 1H), 7.33(d, J=3.9Hz, 1H), 7.57-7.66(m, 3H), 7.95-8.03(m, 3H), 8.26(d, J=0.9Hz, 1H), 8.75(d, J=8.1Hz,1H), 12.91(br s, 1H) 32 B-2 Bn

S 2.76(dd, J=9.4, 13.8Hz, 1H), 3.02(dd, J=4.6, 13.8Hz, 1H), 3.98(m, 1H),7.15-7.30(m, 5H), 7.28(d, J= 3.8Hz, 1H), 7.33(d, J=3.8Hz, 1H),7.56-7.67(m, 3H), 7.94-8.05(m, 3H), 8.26(s, 1H), 8.79(br s, 1H),12.96(br, 1H) 33 B-3 (Indole- 3- yl)methyl

R 2.95(dd, J=8.1, 14.1Hz, 1H), 3.14(dd, J=5.7, 14.1Hz, 1H), 4.00(dd,J=6.3, 7.2Hz, 1H), 6.97(t, J=7.5Hz, 1H), 7.06(t, J=7.2Hz, 1H), 7.12(d,J=2.4Hz, 1H), 7.23(d, J=3.9Hz, 1H), 7.28(d, J=3.9Hz, 1H), 7.33(d,J=8.1Hz, 2H), 7.43(d, J= 7.5Hz, 1H), 7.57-7.67(m, 3H), 7.95- 8.03(m,3H), 8.25(s, 1H), 8.58(br s, 1H), 10.83(s, 1H) 34 B-4 i-Pr

R 0.83(d, J=6.9Hz, 3H), 0.88(d, J= 6.6Hz, 3H), 2.01(m, 1H), 3.64(m, 1H),7.46(d, J=3.9Hz, 1H), 7.54(d, J= 3.9Hz, 1H), 7.57-7.66(m, 3H), 7.94-8.02(m, 3H), 8.26(d, J=1.2Hz, 1H), 8.50(d, J=9.0Hz, 1H), 12.77(br s, 1H)35 B-5 i-Pr

S 0.83(d, J=6.6Hz, 3H), 0.88(d, J=7.0Hz, 3H), 2.02(m, 1H), 3.64(s, 1H),7.46(d, J=4.0Hz, 1H), 7.54(d, J=4.0Hz, 1H), 7.58-7.66(m, 3H),7.96-8.02(m, 3H), 8.27(s, 1H), 8.52(brs, 1H), 12.80(brs, 1H) 36 B-6 Me

R 1.25(d, J=7.2Hz, 3H), 3.91(m, 1H), 7.48(d, J=3.9Hz, 1H), 7.55-7.67(m,4H), 7.95-8.02(m, 3H), 8.26(s, 1H), 8.63(d, J=6.9Hz, 1H), 12.81(br s,1H) 37 B-7 Me

S 1.24(d, J=7.2Hz, 3H), 3.89(s, 1H), 7.48(d, J=4.0Hz, 1H), 7.56-7.66(m,4H), 7.96-8.02(m, 3H), 8.27(s, 1H), 8.62(brs, 1H), 12.79(brs, 1H)

TABLE 7 Example Compound No. No. R² R⁶ * ¹H-NMR (DMSO-d₆) 38 B-8 4-OH—Ph

R 4.87(s, 1H), 6.68(d, J=8.4Hz, 2H), 7.13(d, J=8.7Hz, 2H), 7.39(d, J=3.9Hz, 1H), 7.46(d, J=3.9Hz, 1H), 7.59-7.65(m, 3H), 7.96-8.01(m, 3H),8.25(s, 1H), 9.01(s, 1H), 9.49(s, 1H), 12.94(br s, 1H) 39 B-9 H

3.73(s, 2H), 7.49(d, J=3.9Hz, 1H), 7.57-7.66(m, 4H), 7.95-8.02(m, 3H),8.26(s, 1H), 8.53(br s, 1H), 12.82(br s, 1H) 40 B-10 MeS—CH₂—CH₂—

R 1.7-2.1(m, 2H), 2.00(s, 3H), 2.3- 2.6(m, 2H), 3.97(s, 1H), 7.4-7.7(m,5H), 7.9-8.1(m, 3H), 8.26(s, 1H), 8.65(br s, 1H), 12.78(br s, 1H). 41B-11 MeS—CH₂—CH₂—

S 1.76-1.93(m, 2H), 2.00(s, 3H), 2.35- 2.50(m, 2H), 3.97(s, 1H), 7.47(d,J= 3.8Hz, 1H), 7.54-7.66(m, 4H), 7.96- 8.02(m, 3H), 8.26(s, 1H), 8.65(brs, 1H), 12.80(br s, 1H) 42 B-12 HOOC—CH₂—

R 2.4-2.8(m, 2H), 4.19(s, 1H), 7.40- 7.70(m, 5H), 7.85-8.06(m, 3H),8.27(s, 1H), 8.68(br s, 1H), 12.74(br s, 2H). 43 B-13 i-Bu

R 0.79(d, J=6.3Hz, 3H), 0.86(d, J=6.6Hz, 3H), 1.37-1.54(m, 2H), 1.64(m,1H), 3.78(m, 1H), 7.47(d, J=3.9Hz, 1H), 7.54(d, J=3.9Hz, 1H),7.57-7.67(m, 3H), 7.94-8.03(m, 3H), 8.26(s, 1H), 8.63(d, J=9.0Hz, 1H),12.79(br s, 1H) 44 B-14 4-OH— Bn

R 2.76(dd, J=9.3, 13.5Hz, 1H), 3.01 (dd, J=4.8, 13.5Hz, 1H), 3.90(m,1H), 6.65(d, J=8.4Hz, 2H), 6.97(d, J=8.4Hz, 2H), 7.31(d, J=3.9Hz, 1H),7.35(d, J=3.9Hz, 1H), 7.56-7.67(m, 3H), 7.94-8.03(m, 3H), 8.26(s, 1H),8.72(d, J=8.1Hz, 1H), 9.26(s, 1H), 12.86(br s, 1H) 45 B-15 HOOC—CH₂—CH₂—

R 1.71(m, 1H), 1.93(m, 1H), 2.27(t, J=7.5Hz, 2H), 3.89(dd, J=4.8, 8.7Hz,1H), 7.47(d, J=3.9Hz, 1H), 7.54(d, J=3.9Hz, 1H), 7.58-7.67(m, 3H),7.94-8.03(m, 3H), 8.27(s, 1H), 8.66(br s, 1H), 12.57(br s, 2H)

TABLE 8 Example Compound No. No. R² R⁶ * ¹H-NMR (DMSO-d₆) 46 B-16 Bn

R 2.76(dd, J=9.3, 13.5Hz, 1H), 3.01(dd, J=4.8, 13.5Hz, 1H), 3.90(s, 3H),3.98(m, 1H), 7.16-7.27(m, 6H), 7.27(d, J=3.9Hz, 1H), 7.30(d, J= 3.9Hz,1H), 7.40(d, J=2.4Hz, 1H), 7.59(dd, J=1.8, 8.7Hz, 1H), 7.89(dd, J=5.1,8.7Hz, 2H), 8.17(s, 1H), 8.77(d, J=8.4Hz, 1H), 12.96(br s, 1H) 47 B-17Bn

R 2.77(dd, J=9.9, 13.8Hz, 1H), 3.03 (dd, J=4.5, 13.5Hz, 1H), 3.89(brs,1H), 7.15-7.30(m, 5H), 7.32(d, J= 3.9Hz, 1H), 7.43(d, J=3.9Hz, 1H),7.57- 7.76(m, 3H), 7.88(d, J=7.2Hz, 1H), 8.05(d, J=7.8Hz, 1H), 8.08(d,J= 8.1Hz, 1H), 8.29(d, J=7.8Hz, 1H), 8.78(d, J=7.8Hz, 1H), 12.95(brs,1H) 48 B-18 Bn

R 2.76(dd, J=9.6, 14.0Hz, 1H), 3.03(dd, J=4.6, 14.0Hz, 1H), 4.01(m, 1H),7.15-7.30(m, 5H), 7.32(d, J= 4.0Hz, 1H), 7.47(d, J=4.0Hz, 1H),7.64-7.90(m, 3H), 8.05(d, J=8.4Hz, 2H), 8.48(d, J=8.4Hz, 2H), 9.80(br s,1H), 12.85(br, 1H) 49 B-19 Bn

R 2.75(dd, J=9.6, 13.8Hz, 1H), 3.00(dd, J=4.8, 13.5Hz, 1H), 3.94(br s,1H), 6.11(s, 2H), 7.00(d, J=8.1Hz, 1H), 7.12-7.26(m, 9H), 8.71(br s,1H), 12.89(br s, 1H) 50 B-20 Bn

S 2.75(dd, J=9.3, 13.2Hz, 1H), 3.00(dd, J=5.1, 13.8Hz, 1H), 3.94(br s,1H), 6.11(s, 2H), 7.00(d, J=7.7Hz, 1H), 7.12-7.21(m, 9H), 8.71(br s,1H), 12.89(br s, 1H) 51 B-21 H

3.70(s, 2H), 6.11(s, 2H), 7.00(d, J= 8.1Hz, 1H), 7.14(m, 1H), 7.16(s,1H), 7.38(d, J=3.9Hz, 1H), 7.54(d, J= 3.9Hz, 1H), 8.47(s, 1H), 12.82(br,1H) 52 B-22 Me

R 1.22(d, J=7.2Hz, 3H), 3.88(m, 1H), 6.10(s, 2H), 7.00(d, J=8.1Hz, 1H),7.14(m, 1H), 7.16(s, 1H), 7.37(d, J=3.9Hz, 1H), 7.52(d, J=3.9Hz, 1H),8.60(m, 1H), 12.80(br, 1H)

TABLE 9 Example Compound No. No. R² R⁶ * ¹H-NMR (DMSO-d₆) 53 B-23 i-Pr

R 0.82(d, J=6.6Hz, 3H), 0.86(d, J= 6.9Hz, 3H), 2.00(m, 1H), 3.61(dd, J=6.3, 9.3Hz, 1H), 6.11(s, 2H), 7.00(d, J=7.8Hz, 1H), 7.14(m, 1H), 7.16(s,1H), 7.36(d, J=4.5Hz, 1H), 7.49(d, J=4.5Hz, 1H), 8.47(d, J=9.3Hz, 1H),12.77(s, 1H) 54 B-24 i-Bu

R 0.78(d, J=6.6Hz, 3H), 0.85(d, J= 6.6Hz, 3H), 1.44-1.45(m, 2H), 1.61(m,1H), 3.75(brs, 1H), 6.11(s, 2H), 7.00(d, J=8.1Hz, 1H), 7.14(m, 1H),7.36(d, J=3.9Hz, 1H), 7.49(d, J=3.9Hz, 1H), 8.60(brs, 1H), 12.78(br, 1H)55 B-25 MeS—CH₂—CH₂—

R 1.70-1.95(m, 2H), 1.98(s, 3H), 2.33- 2.45(m, 2H), 3.94(m, 1H), 6.10(s,2H), 7.00(d, J=7.8Hz, 1H), 7.12(m, 1H), 7.16(s, 1H), 7.37(d, J=3.9Hz,1H), 7.50(d, J=3.9Hz, 1H), 8.63(d, J=9.0Hz, 1H), 12.90(brs, 1H) 56 B-26HOOC—CH₂—

R 2.47(dd, J=6.3, 16.2Hz, 1H), 2.68(dd, J=6.3, 16.2Hz, 1H), 4.17(m, 1H),6.10(s, 2H), 7.00(d, J=8.1Hz, 1H), 7.14(m, 2H), 7.36(d, J=3.9Hz, 1H),7.51(d, J=3.9Hz, 1H), 8.62(m, 1H), 12.70(br, 2H) 57 B-27 Indole- 3-yl)methyl

58 B-28 i-Pr

R 0.81(s, 3H), 0.86(s, 3H), 1.99(m, 1H), 3.60(m, 1H), 4.24-4.33(m, 4H),6.92(dd, J=0.3, 8.1Hz, 1H), 7.04-7.12(m, 2H), 7.35(d, J=3.9Hz, 1H),7.48(d, J=3.9Hz, 1H), 8.47(d, J=9.6Hz, 1H), 12.76(br s, 1H) 59 B-29 Bn

R 2.74(dd, J=9.6, 13.5Hz, 1H), 3.00(dd, J=4.8, 13.5Hz, 1H), 3.95(m, 1H),4.20-4.35(m, 4H), 6.93(d, J=8.1Hz, 1H), 7.04-7.30(m, 9H), 8.76(d,J=8.1Hz, 1H), 12.95(br s, 1H)

TABLE 10

Exam- ple Compound No. No. R² * ¹H-NMR (DMSO-d₆) 60 C-1 Bn R 2.76(dd,J=9.6, 13.5Hz, 1H), 3.00(dd, J=4.8, 13.5Hz, 1H), 3.97(brs, 1H),7.05-7.21(m, 5H), 7.64-7.67(m, 2H), 7.86(d, J=8.7Hz, 2H), 8.06(m, 1H),8.17-8.31(m, 5H), 8.59(d, J= 6.6Hz, 1H), 8.85(s, 1H), 12.95(brs, 1H) 61C-2 Bn S 2.76(dd, J=9.3, 13.5Hz, 1H), 3.00(dd, J=5.4, 13.8Hz, 1H),3.98(brs, 1H), 7.10-7.21(m, 5H), 7.63-7.69(m, 2H), 7.86(d, J=9.0Hz, 2H),8.06(m, 1H), 8.16-8.31(m, 5H), 8.56(s, 1H), 8.85(s, 1H), 12.92(brs, 1H)

TABLE 11

Example Compound No. No. R² * ¹H-NMR (DMSO-d₆) 62 D-1 Bn R 2.74(dd,J=8.6, 13.5Hz, 1H), 2.95(dd, J=5.8, 13.5Hz, 1H), 3.89(m, 1H),7.10-7.30(m, 5H), 7.58(d, J=8.8Hz, 2H), 7.60-7.72(m, 2H), 7.91(d,J=8.8Hz, 2H), 7.99-8.22(m, 5H), 8.61(s, 1H), 10.73(s, 1H), 12.73(br, 1H)63 D-2 Bn S 2.74(dd, J=8.4, 13.5Hz, 1H), 2.95(dd, J=5.8, 13.5Hz, 1H),3.90(m, 1H), 7.10-7.30(m, 5H), 7.59(d, J=8.8Hz, 2H), 7.60-7.72(m, 2H),7.91(d, J=8.8Hz, 2H), 8.00-8.20(m, 5H), 8.61(s, 1H), 10.72(s, 1H),12.73(br, 1H)

TABLE 12

Example Compound No. No. R² * ¹H-NMR (DMSO-d₆) 64 E-1 Bn R 2.76(dd,J=9.3, 13.8Hz, 1H), 2.99(dd, J=5.4, 13.5Hz, 1H), 3.97(m, 1H),7.13-7.22(m, 5H), 7.66-7.75(m, 2H), 7.79(d, J=8.7Hz, 2H), 8.09(d,J=7.2Hz, 1H), 8.17(d, J=8.1Hz, 2H), 8.22-8.28(m, 3H), 8.54(d, J=9.6Hz,1H), 8.93(s, 1H), 12.82(br s, 1H) 65 E-2 Bn S 2.75(dd, J=9.6, 14.0Hz,1H), 3.00(dd, J=4.8, 13.2Hz, 1H), 3.96(m, 1H), 7.10-7.21(m, 5H),7.60-7.81(m, 5H), 8.07-8.28(m, 7H), 8.55(d, J=8.8Hz, 1H), 8.93(s, 1H),12.83(br s, 1H) 66 E-3 H 3.70(s, 2H), 7.66-7.77(m, 2H), 8.04(d, J=8.7Hz,2H), 8.09(d, J=7.8Hz, 1H), 8.18-8.36(m, 6H), 8.91(s, 1H), 12.71(br s,1H) 67 E-4 Me R 1.21(d, J=6.9Hz, 3H), 3.88(m, 1H), 7.66-7.77(m, 2H),8.00-8.06(m, 2H), 8.09(d, J=7.8Hz, 1H), 8.18-8.27(m, 3H), 8.29-8.34(m,2H), 8.39(d, J=7.8Hz, 1H), 8.92(s, 1H), 12.61(br s, 1H) 68 E-5 Me S1.21(d, J=6.6Hz, 3H), 3.88(m, 1H), 7.66-7.77(m, 2H), 8.03(d, J=8.7Hz,2H), 8.08(d, J=7.2Hz, 1H), 8.18-8.27(m, 3H), 8.32(d, J=8.7Hz, 2H),8.39(d, J=7.5Hz, 1H), 8.91(s, 1H), 12.68(br s, 1H) 69 E-6 i-Pr R 0.82(d,J=6.6H, 3H), 0.86(d, J=6.9Hz, 3H), 1.99(m, 1H), 3.61(m, 1H),7.66-7.77(m, 2H), 8.02(d, J=8.7Hz, 2H), 8.09(d, J=7.5Hz, 1H),8.18-8.33(m, 6H), 8.92(s, 1H), 12.67(br s, 1H) 70 E-7 i-Pr S 0.82(d,J=6.6H, 3H), 0.86(d, J=6.9Hz, 3H), 1.98(m, 1H), 3.61(t, J=6.9Hz, 1H),7.66-7.77(m, 2H), 8.00-8.05(m, 2H), 8.09(d, J=7.8Hz, 1H), 8.18-8.33(m,6H), 8.92(s, 1H), 12.67(br s, 1H)

TABLE 13 Example Compound No. No. R² * ¹H-NMR (DMSO-d₆) 71 E-8 i-Bu R0.75(d, J=6.3Hz, 3H), 0.84(d, J=6.6Hz, 3H), 1.35-1.52(m, 2H), 1.60 (m,1H), 3.75(m, 1H), 7.66-7.77(m, 2H), 8.02(d, J=8.4Hz, 2H), 8.09(d,J=8.1Hz, 1H), 8.18-8.27(m, 3H), 8.31 (d, J=8.4Hz, 2H), 8.38(d, J=8.4Hz,1H), 8.92(s, 1H), 12.64(br s, 1H) 72 E-9 i-Bu S 0.75(d, J=6.3Hz, 3H),0.84(d, J=6.6Hz, 3H), 1.35-1.52(m, 2H), 1.61 (m, 1H), 3.76(m, 1H),7.66-7.77(m, 2H), 8.02(d, J=8.4Hz, 2H), 8.09(d, J = 7.2Hz, 1H),8.18-8.28(m, 3H), 8.31 (d, J=8.4Hz, 2H), 8.38(d, J=7.8Hz, 1H), 8.92(s,1H), 12.63(br s, 1H) 73  E-10 (Indole- R 2.90(dd, J=8.4, 14.4Hz, 1H),3.11(d, 3- J=5.7, 14.4Hz, 1H), 4.00(dt, yl)methyl J=8.4, 5.7Hz, 1H),6.88-7.00(m, 2H), 7.09(d, J=2.4Hz, 1H), 7.21(d, J=7.5Hz, 1H), 7.35(d,J=7.2Hz, 1H), 7.67-7.77(m, 4H), 8.05(d, J=8.7Hz, 2H), 8.09(d, J=7.8Hz,1H), 8.19-8.29 (m, 3H), 8.47(d, J=8.4Hz, 1H), 8.93 (s, 1H), 10.77(d,J=1.2Hz, 1H), 12.72 (br s, 1H)

TABLE 14

Example Compound No. No. R² * ¹H-NMR (DMSO-d₆) 74 F-1 Bn R 2.76(dd,J=9.9, 13.8Hz, 1H), 3.00(d, J=5.1, 13.8Hz, 1H), 3.99(m, 1H),7.10-7.22(m, 5H), 7.62-7.71(m, 2H), 7.82(d, J=8.4Hz, 2H), 8.05(m, 1H),8.12-8.22(m, 3H), 8.25(d, J=8.4Hz, 2H), 8.61(d, J=8.4Hz, 1H), 8.77(s,1H), 12.84(br s, 1H) 75 F-2 Bn S 2.76(dd, J=9.6, 13.8Hz, 1H), 3.00(d,J=5.1, 13.8Hz, 1H), 3.99(m, 1H), 7.10-7.23(m, 5H), 7.62-7.71(m, 2H),7.82(d, J=8.4Hz, 2H), 8.05(m, 1H), 8.12-8.22(m, 3H), 8.25(d, J=8.4Hz,2H), 8.62(d, J=9.3Hz, 1H), 8.77(s, 1H), 12.85(br s, 1H)

TABLE 15

Example Compound No. No. R² * ¹H-NMR (DMSO-d₆) 76 G-1 i-Pr R 0.82(d,J=6.9Hz, 3H), 0.86(d, J=6.9Hz, 3H), 1.99(m, 1H), 3.61(m, 1H), 7.69(m,2H), 8.00-8.10(m, 3H), 8.10-8.40(m, 6H), 8.82(s, 1H), 12.67(br s, 1H)

Test Example 1 Isolation and Purification of MMP

MMP-1 was purchased from Yagai.

MMP-2 was purchased from Calbiochem-Novabiochem International, Inc.

In regard to MMP-8, catalytic domain (⁹⁹Phe˜²⁶²Gly) was amplified withPCR using commercial available Human Bone Marrow cDNA. This was clonedin Escherichia. coli expression vector pTrc99AHE inserted with His-tagsequence and enterokinase digestion-site, induced and expressed by IPTG(Isopropyl-β-D-thiogalactopyranoside) and expressed in a insolublefraction (Than F. Ho, M. Walid Qoronfleh, Robert C. Wahl, Trica A.Pulvino, Karen J. Vavra, Joe Falvo, Tracey M. Banks, Patricia G. Brakeand Richard B. Ciccarelli: Gene expression, purification andcharacterization of recombinant human neutrophil collagenase. Gene 146,(1994) 297-301, Prepared by the a improved method of this material).Isolation of MMP-8 from insoluble fraction was carried out by dissolvingin modifier (6M urea) by a usual method and purification with metalchelate chromatography. And then removing modifier (6M urea) withdialysis and refolding of the enzyme spontaneously gave activated MMP-8.

MMP-9 was isolated and purified by using a combination of proceduresdescribed in previous reports as follows. Yasunori Okada, Yukio Gonoji,Katsumi Naka, Katsuro Tomita, Isao Nakanishi, Kazushi Iwata, KyokoYamashita, and Taro Hayakawa: Matrix metalloproteinase 9 (92-kDagelatinase/type IV collagenase) from HT1080 human fibrosarcoma cells.Purification and activation of the precursor and enzymic properties. J.Biol. Chem., 267 (1.992) 21712-21719. Yasunori Okada, TatsuhisaMorodomi, Jan J, Enghild, Ko Suzuki, Atsushi Yasui, Isao Nakanishi, GuySalvesen and Hideaki Nagase: Matrix metalloproteinase 2 from humanrheumatoid synovial fibroblasts. Purification and activation of theprecursor and enzymic properties. Eur. J. Biochem. 194 (1990) 721-730.Robin V Ward, Rosalind M Hembry, John J Reynolds and Gillian Murphy: Thepurification of tissue inhibitor of metalloproteinase-2 from its 72 kDaprogelatinase complex. Biochem. J. 278 (1991) 179-187.

Briefly, human fibrosarcoma ATCC HT1080 cell line was cultured toconfluent in Dulbecco's Modified Medium (DMEM) containing 10% fetal-calfserum at 37° C. for 48 hours. Subsequently, the medium of confluentculture was changed to serum-free DMEM medium. To obtain MMP-9,Phorbol-12-myristate-13-acetate (TPA) must be added to this serum-freeDMEM medium at a concentration of 50 ng/ml. The TPA treated medium wascentrifuged at 3000 rpm for 15 min and the supernatant was concentratedto 450 ml by a Toyo-Roshi UP-20 apparatus with an ultrafiltrationmembrane. Then, proMMP-9 in this concentrated solution was purified byusing columns of Gelatin-Sepharose and Concanavalin A-Sepharose. Thepool containing proMMP-9 was dialyzed, concentrated (Toyo-Roshi UP-20)and applied to columns of Sephacryl S-200 and Green A matrix for theseparation from TIMPs. The obtained proMMP-9 fraction was activated byTPCK-Trypsin (final conc. 3 μg/μl reaction mix.).

In regard to MMP-12, catalytic domain(¹⁰⁰Phe˜²⁶³Gly) was amplified withRT-PCR from Human Placenta Total RNA. This was cloned in Escherichiacoli expression vector pTrc99AHE inserted with His-tag sequence andenterokinase digestion-site, induced and expressed by IPTG(Isopropyl-β-D-thiogalactopyranoside) and expressed in a insolublefraction. Isolation of MMP-12 from a insoluble fraction was carried outby dissolving in modifier (6M urea) by a usual method and purificationwith metal chelate chromatography (Ni Chelateing Sepharose). And thenremoving modifier (6M urea) with dialysis and refolding of the enzymespontaneously gave activated MMP-12.

In regard to MMP-13, mRNA was prepared from carcinoma cell SW1353derived from human cartilage stimulate by IL-1, TNF and catalytic domain(¹⁰⁴Tyr˜²⁶⁷Gly) was amplified with RT-PCR. This was cloned inEscherichia coli expression vector pTrc99AHE inserted with His-tagsequence and enterokinase digestion-site, induced and expressed by IPTG(Isopropyl-β-D-thiogalactopyranoside) and expressed in a insolublefraction. Isolation of MMP-1.3 from a insoluble fraction was carried outby dissolving in modifier (6M urea) by a usual method and purificationwith metal chelate chromatography (Ni Chelateing Sepharose). And thenremoving modifier (6M urea) with dialyze and refolding of the enzymespontaneously gave activated MMP-13.

Test Example 2 Assay for Inhibitory Activities on Various Type of MMPs

The enzymatic activity on MMPs was analyzed by the method described in“C. Graham Knight, Frances Willenbrock and Gillian Murphy: A novelcoumarin-labelled peptide for sensitive continuous assays of the matrixmetalloproteinases: FEBS LETT., 296, (1992), 263-266”. The substrate:MOCAc-Pro-Leu-Gly-Leu-A₂Pr(DNP)-Ala-Arg-NH₂ was purchased from PeptideInstitute, Inc., Osaka, Japan. The measurement of the inhibitoryactivities (IC₅₀) was carried out by the following four methods;

(A) Reaction with substrate, enzyme (MMPs) and inhibitor

(B) Reaction with substrate and inhibitor, without enzyme

(C) Reaction with substrate and enzyme (MMPs), without inhibitor

(D) Reaction with substrate only

IC₅₀ values were calculated by using the following formula and eachfluorescence values of above four methods (A to D).

% inhibition={1−(A−B)/(C−D)}×100

IC₅₀ means the concentration required to inhibit 50% of the enzymeactivity.

The results are shown in Table 16.

TABLE 16 Compound MMP-1 MMP-2 MMP-8 MMP-9 MMP-12 MMP-13 No. (μM) (μM)(μM) (μM) (μM) (μM) A-1 >10 0.40 0.57 0.77 0.0076 0.30A-2 >10 >10 >10 >10 0.016 >10 A-3 >10 >10 >10 >10 0.021 >10 A-5 >10 0.111.06 0.33 0.014 0.34 A-6 >10 0.40 0.57 0.77 0.0076 0.30 A-8 >10 0.572.44 3.28 0.016 2.77 A-9 >10 0.25 >10 1.80 0.069 2.88 A-10 >10 0.37 4.381.44 0.058 1.55 A-11 >10 0.37 0.58 1.27 0.0059 0.46 A-12 >10 0.37 3.631.79 0.035 1.14 A-15 >10 0.46 >10 0.90 0.032 0.89 A-16 >10 0.11 1.320.62 0.010 0.37 A-17 >10 0.39 0.60 1.06 0.0078 0.37 A-22 >10 0.013 0.0100.30 0.0079 0.037 B-1 >10 0.82 >10 >10 0.042 >10 B-2 >10 >10 >10 >100.24 >10 B-3 >10 0.18 1.40 0.75 0.016 >10 B-4 >10 0.24 0.54 0.53 0.0110.64 B-5 >10 2.23 2.34 3.27 0.082 6.90 B-6 >10 0.35 2.09 0.84 0.023 0.84B-7 >10 2.03 7.79 6.31 0.16 >10 B-8 >10 1.12 2.65 2.11 0.048 2.30B-9 >10 1.27 >10 4.23 0.26 7.18 B-10 >10 0.35 1.00 0.87 0.0088 0.95B-11 >10 1.86 2.89 4.9 0.11 6.14 B-12 >10 1.25 2.60 1.10 0.040 1.40B-17 >10 >10 >10 >10 0.82 >10 C-1 >10 0.14 >10 >10 0.055 0.45C-2 >10 >10 >10 >10 0.14 >10 D-2 >10 0.56 4.51 6.56 0.15 2.33

Test Example 3

Sprague-Dawley male rats (390-430 g initial body weight) were exposeddaily to smoke from commercial filtered cigarettes (30cigarettes/rat/day, 5 days/week, for 7 to 8 weeks) with asmoke-generating and whole-body exposure system. The animals received 30mg/kg p.o. twice daily of compound (B-6), which was suspended with 0.5%methyl cellulose. Vehicle animals received 2 ml/kg of 0.5% methylcellulose. At 16-24 hr after the last exposure with cigarette smoke,anesthesia was induced with intraperitoneal injection of 40 mg/kg ofpentobarbital sodium. Immediately after muscle relaxation withintravenous pancuronium bromide (0.3 mg/rat), animals were mechanicallyventilated with a pressure-limited ventilator and were evaluated dynamiccompliance. After exsanguination, the lung was attached to a glasssyringe via a connector tube and continuously inflated through theairway to a transpulmonary pressure of 30 cmH₂O, deflated them to a Ptpof 0 cmH₂O, and aspirated them to a Ptp of −20 cmH₂O. The change of Ptpand lung volume was monitored and recorded as the deflationpressure-volume (P-V) curve. Static lung compliance defined as the slopeof steep portion of the deflation P-V curve was evaluated. Inspiratorycapacity (IC) defined as the difference in lung volume between totallung capacity at a Ptp of 25 cmH₂O and functional residual capacity at aPtp of 0 cmH₂O was evaluated.

Data are expressed as means ±S.D. Statistical analysis was performedwith one-sided Student's t-test. A value of P<0.05 was consideredsignificant.

The results were shown in Table 17.

TABLE 17 dynamic compliance Static lung compliance Inspiratory capacity(ml/cmH₂O/kg) (ml/cmH₂O/kg) (ml/kg) n = Air exposure 0.84 ± 0.12 2.06 ±0.16 21.77 ± 1.63 8 Cigarette smoke exposure 1.02 ± 0.14 ^(#) 2.36 ±0.38 ^(#) 23.74 ± 2.64 ^(#) 7 (Vehicle) Compound (B-6) 0.96 ± 0.17 2.05± 0.25 * 21.76 ± 1.85 7 Administration ^(#) P < 0.05 vs. Air exposure *P < 0.05 vs. Cigarette smoke exposure

As shown in Table 17, compound (B-6) significantly reduced the increaseof static lung compliance and tended to attenuate the increase ofdynamic compliance and inspiratory capacity by cigarette smoke exposureinthe rats.

FORMULATION EXAMPLE Formulation Example 1

Granules are prepared using the following ingredients.

Ingredients The compound represented  10 mg by the formula (I) Lactose700 mg Corn starch 274 mg HPC-L  16 mg 1000 mg 

The compound represented by the formula (I) and lactose are made passthrough a 60 mesh sieve. Corn starch is made pass through a 120 meshsieve. They are mixed by a twin shell blender. An aqueous solution ofHPC-L (low mucosity hydroxypropylcellulose) is added to the mixture andthe resulting mixture is kneaded, granulated (by the extrusion with poresize 0.5 to 1 mm mesh), and dried. The dried granules thus obtained aresieved by a swing sieve (12/60 mesh) to yield the granules.

Formulation 2

Powders for filling capsules are prepared using the followingingredients.

Ingredients The compound represented by 10 mg the formula (I) Lactose 79mg Corn starch 10 mg Magnesium stearate  1 mg 100 mg 

The compound represented by the formula (I) and lactose are made passthrough a 60 mesh sieve. Corn starch is made pass through a 120 meshsieve. These ingredients and magnesium stearate are mixed by a twinshell blender. 100 mg of the 10-fold trituration is filled into a No. 5hard gelatin capsule.

Formulation 3

Granules for filling capsules are prepared using the followingingredients.

Ingredients The compound represented by 15 mg the formula (I) Lactose 90mg Corn starch 42 mg HPC-L  3 mg 150 mg 

The compound represented by the formula (I) and lactose are made passthrough a 60 mesh sieve. Corn starch is made pass through a 120 meshsieve. After mixing them, an aqueous solution of HPC-L is added to themixture and the resulting mixture is kneaded, granulated, and dried.After the dried granules are lubricated, 150 mg of that are filled intoa No. 4 hard gelatin capsule.

Formulation 4

Tablets are prepared using the following ingredients.

Ingredients The compound represented by 10 mg the formula (I) Lactose 90mg Microcrystal cellulose 30 mg CMC-Na 15 mg Magnesium stearate  5 mg150 mg 

The compound represented by the formula (I), lactose, microcrystalcellulose, and CMC-Na (carboxymethylcellulose sodium salt) are made passthrough a 60 mesh sieve and then mixed. The resulting mixture is mixedwith magnesium stearate to obtain the mixed powder for the tabletformulation. The mixed powder is compressed to yield tablets of 150 mg.

Industrial Applicability

The sulfonamide derivatives of the present invention have inhibitingactivities against the metalloproteinase, especially selectivelyinhibiting activities agaist MMP-12 and are useful as the treating orpreventing agent of chronic obstructive pulmonary disease.

1. A compound of the formula (I):

wherein R¹ is NHOH, hydroxy, or lower alkyloxy; R² is hydrogen atom,optionally substituted lower alkyl, optionally substituted aryl, oroptionally substituted aralkyl; R³ is hydrogen atom, optionallysubstituted lower alkyl, optionally substituted aryl, or optionallysubstituted aralkyl; R⁴ is optionally substituted arylene; R⁵ is a bond,—(CH₂)p—, —CH═CH—, —C≡C—, —CO—, —CO—NH—, —N═N—, —N(R^(A))—, —NH—CO—NH—,—NH—CO—NH—, —O—, —S—, —SO₂—, —SO₂NH—, or —SO₂—NH—N═CH—, wherein R^(A) ishydrogen atom or lower alkyl, p is 1 or
 2. R⁷ is each independentlyhydrogen atom, halogen, lower alkyl, cycloalkyl, lower alkenyl, loweralkynyl, lower alkyloxy, lower alkenyloxy, lower alkylthio,halo(lower)alkyl, hydroxy, carboxy, lower alkyloxycarbonyl,aminocarbonyl, acyl, nitro, cyano, or optionally substituted amino; m is0, 1, 2, or 3, its optically active substance, its prodrug, theirpharmaceutically acceptable salt, or solvate thereof.
 2. A compound ofthe formula (III):

wherein R¹ is NHOH, hydroxy, or lower alkyloxy; R³ is hydrogen atom,optionally substituted lower alkyl, optionally substituted aryl, oroptionally substituted aralkyl; R⁴ is optionally substituted arylene; R⁵is a bond, —(CH₂)p—, —CH═CH—, —C≡C—, —CO—, —CO—NH—, —N—N—, —N(R^(A))—,—NH—CO—NH—, —NH—CO—, —O—, —S—, —SO₂—, —SO₂NH—, or —SO₂—NH—N═CH—, whereinR^(A) is hydrogen atom or lower alkyl, p is 1 or 2; R⁷ is eachindependently hydrogen atom, halogen, lower alkyl, cycloalkyl, loweralkenyl, lower alkynyl, lower alkyloxy, lower alkenyloxy, loweralkylthio, halo(lower)alkyl, hydroxy, carboxy, lower alkyloxycarbonyl,aminocarbonyl, acyl, nitro, cyano, or optionally substituted amino; andm is 0, 1, 2, or 3; R⁸ is hydrogen atom, lower alkyl optionallysubstituted with aminocarbonyl or lower alkylthio, aryl optionallysubstituted with hydroxy, aralkyl optionally substituted with hydroxy,its optically active substance, its prodrug, their pharmaceuticallyacceptable salt, or solvate thereof.
 3. A compound of the formula (IV):

wherein R⁹ is hydrogen atom, methyl, isopropyl, isobutyl,aminocarbonylmethyl, 2-methylthioethyl, 4-hydroxyphenyl, benzyl, or4-hydroxybenzyl; R¹⁰ is 1,4-phenylene; R¹¹ is —C≡C—, CO—NH—, —NHCO—, or—O—, R¹² is each independently hydrogen atom, halogen, lower alkyl,lower alkoxy, halo(lower)alkyl, nitro, cyano, optionally substitutedamino, or hydroxy; m is 0, 1, 2, or 3, its optically active substance,its prodrug, their pharmaceutically acceptable salt, or solvate thereof.4. A pharmaceutical composition comprising a compound of claim 1 as anactive ingredient.
 5. A method for treating a mammal, including a human,to alleviate the pathological effects of chronic obstructive pulmonarydisease, which comprises administration to said mammal of a compound asclaimed in claim 1 in a pharmaceutically effective amount.
 6. A compoundas claimed in claim 1, wherein R⁵ is a bond, —(CH₂)₂—, —CH═CH—, —C≡C—,—CO—, —N═N—, —N(R^(A))—, —NH—CO—NH—, —O—, —S—, —SO₂—, —SO₂NH—,SO₂—NH—N═CH—, wherein R^(A) is hydrogen or lower alkyl; its opticallyactive substance, its prodrug, their pharmaceutically acceptable salt,or solvate thereof.
 7. A compound as claimed in claim 2, wherein R⁵ is abond —(CH₂)₂—, —CH═CH—, —C≡C—, —CO—, —N═N—, —N(R^(A))—, —NH—CO—NH—, —O—,—S—, —SO₂—, —SO₂NH—, —SO₂—NH—N═CH—, where in R^(A) is a hydrogen orlower alkyl; its optically active substance, its prodrug, theirpharmaceutically acceptable salt, or solvate thereof.
 8. A compound asclaimed in claim 3, wherein R¹¹ is —C≡C— or —O—; is optically activesubstance, its prodrug, their pharmaceutically acceptable salt, orsolvate thereof.